10-3781811-A-T

Variant names:

• chr10-3781811-A-T
• rs121909143
• NM_001300.6:c.506T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP2 BP4

The NM_001300.6(KLF6):​c.506T>A​(p.Leu169Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L169P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLF6 NM_001300.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42
• Publications: 3 publications found

Genes affected

KLF6 (HGNC:2235): (KLF transcription factor 6) This gene encodes a member of the Kruppel-like family of transcription factors. The zinc finger protein is a transcriptional activator, and functions as a tumor suppressor. Multiple transcript variants encoding different isoforms have been found for this gene, some of which are implicated in carcinogenesis. [provided by RefSeq, May 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-3781811-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7573.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.8535 (below the threshold of 3.09). Trascript score misZ: 2.6969 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.38323966).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	NM_001300.6	MANE Select	c.506T>A	p.Leu169Gln	missense	Exon 2 of 4	NP_001291.3
	KLF6	NM_001160124.2		c.506T>A	p.Leu169Gln	missense	Exon 2 of 4	NP_001153596.1
	KLF6	NM_001160125.2		c.506T>A	p.Leu169Gln	missense	Exon 2 of 3	NP_001153597.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF6	ENST00000497571.6	TSL:1 MANE Select	c.506T>A	p.Leu169Gln	missense	Exon 2 of 4	ENSP00000419923.1
	KLF6	ENST00000469435.1	TSL:1	c.506T>A	p.Leu169Gln	missense	Exon 2 of 2	ENSP00000419079.1
	KLF6	ENST00000542957.1	TSL:5	c.506T>A	p.Leu169Gln	missense	Exon 2 of 3	ENSP00000445301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.050
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.047	D
Polyphen		0.97	D
Vest4		0.53
MutPred		0.28		Loss of catalytic residue at L169 (P = 0.0761)
MVP		0.52
MPC		1.8
ClinPred		0.98	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.62
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121909143; hg19: chr10-3824003;